This study evaluated the osteogenic differentiation of human mesenchymal stem cells (MSCs), on tyrosine-derived polycarbonates copolymerized with poly(ethylene glycol) (PEG) to determine their potential as a scaffold for bone tissue engineering applications. The addition of PEG in the backbone of polycarbonates has been shown to alter mechanical properties, degradation rates, degree of protein adsorption, and subsequent cell adhesion and motility in mature cell phenotypes. Its effect on MSC behavior is unknown. MSC morphology, motility, proliferation, and osteogenic differentiation were evaluated on polycarbonates containing 0-5% PEG over a 14 day culture. MSCs on polycarbonates containing 0% or 3% PEG content upregulated the expression of osteogenic markers as demonstrated by alkaline phosphatase activity and osteocalcin expression although at different stages in the 14 day culture. Cells on polycarbonates containing no PEG were characterized as having early onset of cell spreading and osteogenic differentiation. Cells on 3% PEG surfaces were delayed in cell spreading and osteogenic differentiation, but had the highest motility as compared with cells on substrates containing no PEG and substrates containing 5% PEG at early time points. Throughout the culture, cells on polycarbonates containing 5% PEG had the lowest levels of osteogenic markers, displayed poor cell-substrate adhesion, and established cell-cell aggregates. Thus, designing substrates with minute variations in PEG may serve as a tool to guide MSC adhesion and motility accompanying osteogenic differentiation, and may be beneficial for abundant bone tissue formation in vivo.